tbuckley/cabot-search huggingface dataset:
Plasma arginine as a candidate predictive biomarker for response to immune checkpoint inhibition (ICI) in metastatic colorectal cancer (mCRC): Analysis of the CCTG CO.26 trial.
Authors: Lucy Xiaolu Ma, Jonathan M. Loree, Derek J. Jonker, Hagen Fritz Kennecke, Scott R. Berry, Felix Couture, Chaudhary E. Ahmad, John R. Goffin, Petr Kavan, Mohammed Harb, Bruce Colwell, Setareh Samimi, Benoit Samson, Tahir Abbas, Nathalie Aucoin, Francine Aubin, Sheryl L. Koski, Dongsheng Tu, Christopher J. O'Callaghan, Eric X Chen
Journal: Journal of Clinical Oncology (2023)

3545 Background: Nutritional stress is one of the mechanisms used by tumour cells to evade the immune system. Arginine (ARG), an amino acid involved in several cellular functions including immunomodulation, is important in regulating T-lymphocyte cell activity and the anti-tumour response. ARG deficiency in the tumour microenvironment has been shown to impair T-cell response while ARG supplementation may promote anti-tumour immune activity. In this exploratory post-hoc analysis of the Phase II CO.26 trial (NCT02870920), we investigated the role of plasma ARG in predicting response to ICI in patients (pts) with refractory mCRC. Methods: CO.26 was a phase II trial which randomized pts with refractory mCRC to durvalumab plus tremelimumab (D+T) versus best supportive care (BSC). Plasma ARG concentrations were determined from blood samples pre-treatment using HPLC-tandem mass spectrometry. The median plasma ARG value was used as a cut-off stratifying pts into ARG-high (≥10650 ng/ml) versus ARG-low ( &lt; 10650 ng/ml) groups. Progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared between groups using the log-rank test. Cox proportional hazard models were used to analyze prognostic and predictive impacts of ARG on PFS and OS. Results: Of 180 pts enrolled in CO.26, 162 pts (N = 115 treated with D+T and 47 BSC) had pre-treatment blood samples for baseline ARG analysis. There were no significant differences in baseline characteristics between pts included in this analysis and the total study pts, or between ARG-high and ARG-low pts. In pts treated with D+T, ARG-high was associated with more favourable prognosis (ARG-high median OS 7.62 months vs. ARG-low 5.49 months, multivariable hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.40-0.91, p = 0.016). In ARG-high pts, D+T significantly improved OS (median OS 7.62 months with D+T vs 3.61 months BSC; HR 0.61, 95% CI 0.37-0.99, p = 0.04). In ARG-low pts there was no OS benefit with D+T (median OS 5.49 months D+T vs 4.27 months BSC; HR 0.84, 95% CI 0.50-1.41, p = 0.51. Interaction p = 0.037). Baseline ARG values had no association with PFS or disease control rate. Conclusions: Baseline plasma ARG was prognostic in pts with mCRC treated with D+T, and high ARG was predictive of improved OS with ICI. Prospective studies should be done to validate ARG as a biomarker identifying mCRC pts likely to derive benefit from ICI. Therapeutic approaches targeting the ARG pathway should be investigated in future studies.
Machine learning to predict future PSA in patients with prostate cancer managed with active surveillance.
Authors: Aziz Ayed, Claire-Alix Saillard, John A. Onofrey, Intae Moon, Steven Lee Chang, Adam Scott Feldman, Madhur Nayan
Journal: Journal of Clinical Oncology (2023)

e17098 Background: Active surveillance (AS) for prostate cancer (PCa) requires serial assessments and there is a need to optimize resource utilization by personalizing AS. Evaluating serial PSA values is fundamental in AS and a model predicting future PSA may aid decision-making on optimizing the timing of the subsequent assessment. In this study, we use a machine learning (ML) approach to predict future PSA in AS patients. Methods: We searched electronic health record data at two tertiary academic centers for patients with a diagnosis of PCa or reason for visit related to PCa (e.g. elevated PSA) between 1990 and 2020. Within this group, we identified patients diagnosed with PCa and managed with AS. We trained different ML models (Table 1) to predict the next PSA value given a sequence of historical PSAs and expected date of next PSA assessment, and compared this prediction to the ground truth (actual PSA measured). We augmented the model with clinical features (age, prostate volume, and BMI). We compared the ML models to a baseline method that considers a patient-specific constant slope based on prior PSA values. The test set consisted of AS patients only (10% of all AS patients), not used in training. The dataset was split patient-wise. The primary performance metric was root-mean-square error (RMSE). We compared training using AS patients only to using all patients, still testing on AS patients only. We evaluated feature importance to facilitate model interpretability. Results: We identified 4269 patients (totaling 33371 PSA values) with at least 3 PSA values and complete data for the clinical features. Of these, 1134 were on AS (totaling 10358 PSA values). On average, AS patients were 65 years old (± 7 [standard deviation]), with a mean PSA of 6.5 ng/mL (± 6.4), prostate volume of 48g (± 27) and BMI of 28 kg/m2 (± 5), at diagnosis. The best performing model was the Gradient Boosting Regression model that was trained in the heterogeneous sample of all patients (including those not on AS) (Table 1). Evaluation of feature importance found that increasing the number of previous PSA measurements as input to the model further reduced the RMSE. Conclusions: Our study used machine learning to predict future PSA in PCa patients on AS. We also demonstrate that for our best performing model, a heterogeneous training sample further improved performance. While our model requires further validation, a robust similar model may be useful as a decision-aid tool to personalize AS and optimize resource-utilization. We have deployed our model at https://psa-evolution.streamlit.app/ . [Table: see text]
Impact of patient travel time on disparities in precision oncology clinical trials.
Authors: Yuji Uehara, Takafumi Koyama, Yuki Katsuya, Jun Sato, Noboru Yamamoto
Journal: Journal of Clinical Oncology (2023)

3113 Background: Precision oncology revolutionizes cancer care, allowing personalized treatments to improve outcomes. Precision oncology often entails participation in genotype-matched clinical trials, resulting in referrals from institutions providing comprehensive genomic profiling (CGP) testing to those conducting these trials. It is still being determined whether there are regional disparities in precision oncology. Methods: We conducted a retrospective review of 1127 patients (pts) referred to National Cancer Center Hospital (NCCH) for participation in genotype-matched clinical trials following CGP testing performed between June 2020 and June 2022. Travel distance and time were calculated utilizing Google Maps from the patient's residence to the NCCH. A total of 23 covariates were preselected and dichotomized per previous research or expert consensus as follows: age, sex, performance status, body mass index, tumor type, number of lines of prior therapies, number of metastatic sites, liver metastases, brain metastases, pleural or peritoneal effusions, biopsiability, neutrophil, hemoglobin, platelet, albumin, creatinine, total bilirubin, LDH, AST, CRP, place of residence (urban vs. rural), referring hospitals, and household income. All independent variables associated with participation in genotype-matched trials (P &lt; 0.20) were included in a multivariable model, and variable importance was calculated using a machine learning (ML) model (gradient-boosted decision tree). Results: A total of 127 (11%) of 1127 pts were enrolled in the genotype-matched trials. Of 127 pts, 82 (65%) and 45 (35%) participated in phase 1 trials and phase 2/3 trials, respectively. The overall median travel distance and time were 38 km (interquartile range [IQR] 21–107) and 55 minutes (IQR 35–110), respectively. In multivariable regression, travel distance (≥100km vs. &lt;100km) was not associated with the proportion of genotype-matched trial participation (9% vs. 12%; odds ratio [OR], 0.68; 95% confidence interval [CI], 0.42–1.07; P = 0.11); however, in pts with travel time ≥120 minutes, the proportion of genotype-matched trial participation was significantly lower than those with travel time &lt; 120 minutes (7% vs. 13%; OR, 0.54; 95% CI, 0.32–0.89; P = 0.019). The proportion of genotype-matched trial participation decreased as travel time increased from &lt;40 minutes to 40–120 minutes to ≥120 minutes (13% vs. 12% vs. 7%, respectively; OR, 0.67; 95% CI, 0.50–0.88; P = 0.006). Travel time was also identified as an important factor in the ML model, whereas low-income and residence in rural areas were of minor importance. Conclusions: Patients with travel time ≥120 minutes were less likely to participate in genotype-matched clinical trials than those with travel time &lt;120 minutes. Regional disparities may be creating inequities in precision oncology, which warrant immediate action, including decentralization of clinical trials.
Association between autologous transfusion and recurrence-free survival in patients with hepatocellular carcinoma after resection: A prospective nonrandomized controlled trial.
Authors: Jian-Hong Zhong, Si Xie, Jian-Li Huang, Da-Long Yang, Zu-Shun Chen, Liang Ma
Journal: Journal of Clinical Oncology (2023)

e16206 Background: To investigate whether preoperative stored autologous transfusion has a significant effect on recurrence-free survival of patients with primary hepatocellular carcinoma (HCC). Methods: Recurrence-free survival (RFS), overall survival, and perioperative morbidity were compared among patients with or without autologous transfusion at our medical center between January 2019 and December 2021. Patients who received autologous transfusion were matched based on propensity scores to patients who did not, in order to reduce confounding due to baseline differences. This study was registered on ClinicalTrials.gov (NCT02654028). Results: Of the 618 patients in the analysis, 399 (64.6%) received autologous transfusion and 219 (35.4%) did not receive autologous transfusion. By 30 July 2022, the median RFS time had been achieved. Patients with or without autologous transfusion had similar RFS before (hazard ratio 1.01, 95%CI 0.82-1.24) or after propensity score analysis (hazard ratio 1.04, 95%CI 0.82-1.31). However, the median overall survival was not achieved. Patients with or without autologous transfusion also had similar overall survival before (hazard ratio 1.15, 95%CI 0.84-1.56) or after propensity score analysis (hazard ratio 1.26, 95%CI 0.88-1.79). Moreover, subgroup analyses found that patients with or without autologous transfusion had similar RFS or overall survival among those with early, intermediate, or advanced stage disease. The two groups also had similar rates of perioperative mortality and morbidity. Conclusions: Preoperative stored autotransfusion had no significant effect on survival in patients with HCC who underwent liver resection. Clinical trial information: NCT02654028 .
Prognostic relevance of 3q amplification (AMP) in a racially diverse patient population with advanced squamous cell carcinoma of the lung.
Authors: Fawzi Abu Rous, Pin Li, Shannon Carskadon, Radhika Gutta, Bindu Rani Potugari, Shirish M. Gadgeel, Nallasivam Palanisamy
Journal: Journal of Clinical Oncology (2023)

e15142 Background: Amplification (AMP) of 3q is the most common genetic alteration in squamous cell carcinoma of the lung (LUSC) with the most frequently amplified region being 3q26-3q28. It represents one of the most striking molecular differences between LUSC and adenocarcinoma. We identified a minimal common region (MCR) of AMP constituted by 25 genes within a large amplicon on chromosome 3q by analyzing data of 476 patients with LUSC from The Cancer Genome Atlas (TCGA) and extracting copy number alteration data from cBioPortal. Full 25-gene MCR AMP was detected in 46.4% of the cases and was associated with better disease-specific survival (NR vs 9.25 years, 95% CI [5.24-NR]; p = 0.011) and progression-free interval (8 vs 4.9 years, 95% [3.5-NR]; p = 0.020). The TCGA cohort was mainly comprised of Caucasians (69.7%) and patients with early-stage disease (98.7%). We conducted a retrospective pilot analysis to validate the prognostic value of MCR AMP using a racially diverse cohort with advanced LUSC. Methods: We retrieved tissue samples for 33 patients with stage III or stage IV LUSC and collected retrospective data from Electronic Medical Records. The pathologist reviewed the slides to ensure the adequacy of tumor tissue. MCR AMP was evaluated via laboratory- developed FISH probe spanning MCR region. FISH test that showed a cluster of signals with more than 4 copies was regarded as positive; we used a control probe for the 3p arm which is typically not amplified in LUSC. Results: The mean age of the cohort was 69.1 years, 57.6% were males, 39.4% were African Americans (AA) and 54.5% were Caucasians, 66.7% had stage 3, and 33.3% had stage 4. Only 6.1% were never smokers and 84.8% were former smokers. MCR AMP was detected in 54.5% (n = 18) of the cases. PD-L1 status was available for 21 (63%) cases, 6 cases (3 had MCR AMP) were PD-L1 negative (TPS &lt; 1%), and 15 cases (9 had MCR AMP) were PD-L1 positive (TPS &gt; 1%). Consistent with the results observed in the TCGA cohort, MCR amplified cases had a trend towards better overall survival (OS) compared to non-amplified cases (1.74 vs 0.91 years; HR = 0.57, 95% CI [0.26-1.24], p = 0.15) as well as a trend towards better progression-free survival (PFS) (0.90 vs 0.74 years; HR = 0.88, 95% CI [0.43-1.81], p = 0.73). Conclusions: This pilot analysis shows that MCR AMP carries a prognostic value in a racially diverse patient population with advanced LUSC, similar to our observations in the TCGA cohort. Further validation in a large cohort is in progress.
An estimate of the burden of pancreatic cancer globally and its comparison with different WHO regions using Global Burden of Disease Database: A retrospective population-based analysis.
Authors: Shoheera Punjwani, Aunchalee Jaroenlapnopparat, Chinmay Jani, Harpreet Singh, Dominic C Marshall, Justin D Salciccioli, Joseph Shalhoub
Journal: Journal of Clinical Oncology (2023)

e16321 Background: Pancreatic cancer is a highly aggressive malignancy and is the fourth leading cause of cancer-related deaths in the United States and seventh globally. Most pancreatic cancers are adenocarcinomas that have poor prognoses. The highest incidence is reported between 65-69 in men and 75-79 in women. Worldwide, both incidence and mortality are increasing. We must evaluate the global and regional patterns to understand the impact of risk factors and develop early detection methods and treatments. Methods: We extracted pancreatic cancer mortality data from the Global Burden of Disease database based on the International Classification of Diseases versions 10 and 9. Age-standardized incidence rates (ASIR), age-standardized mortality rates (ASMR), the age-specific death rate(ASDR), mortality-incidence ratio (MIR) and disability-adjusted life years (DALYs) were extracted for global as well as six WHO regions (Africa, Region of the Americas, South-East Asia, Europe, Eastern Mediterranean, Western Pacific) for both for the years 1990 and 2019. Joinpoint regression analysis was used to describe trends. Results: Between 1990 and 2019, pancreatic cancer ASIRs, ASMRs, and DALYs increased among the six regions in both males and females. Globally, ASIR, ASMR and DALY increased in males (+25.02%, +23.40%, +19.97%) and females (+26.35%, +24.30%, +22.08%). However, MIR decreased globally (males: -1.29%, females: -1.62%). The Eastern Mediterranean region showed the highest percentage change in ASIR, ASMR, and DALY in both males (+110.45%, +106.53%, +103.24%, respectively) and females (+140.20, +135.48%, +127.20% respectively), followed by the South-East Asia region (males: +71.38%, +70.03%, +63.80% respectively; females: +114.20%, +111.78%, +106.91% respectively). MIRs showed decreased trends among all six regions in both sexes. Europe region showed the highest decrease in males (-1.91%) and females (-3.09%). Conclusions: Overall, we reported the increasing disease burden of pancreatic cancer globally between 1990 and 2019. ASIRs, ASMRs and DALYs all increased throughout the six regions in both sexes, with the Eastern Mediterranean region being the highest. MIRs showed a global decreasing trend in both sexes, which may indicate an overall improvement in pancreatic cancer clinical care.
Donafenib combined with camrelizumab and transarterial chemoembolization (TACE) as conversion therapy for unresectable hepatocellular carcinoma (uHCC): A prospective, single-arm, phase II study.
Authors: Yajuan Cao, Xuebin Zhang, Yang Yue, Jin Peng, Binghua Li, Jiong Shi, Min Tang, Chaobo Chen, Ke Su, Laizhu Zhang, Chunxiao Cheng, Decai Yu
Journal: Journal of Clinical Oncology (2023)

e16203 Background: Approximately 64% of Chinese patients with HCC were evaluated as China Liver Cancer Stage (CNLC) II/III tumors, equivalent to Barcelona Liver Cancer Stage (BCLC) B or C. The conversion of an initially unresectable HCC (uHCC) to a resectable HCC may be an optimal approach to achieve better outcomes. Although donafenib, camrelizumab and transarterial chemoembolization (TACE) were recommended for uHCC in Chinese guidelines, the effect of these agents in the pre-operative setting was unclear. The present study was to assess the feasibility and safety of donafenib plus camrelizumab with TACE as conversion therapy in patients with uHCC. Methods: Patients were enrolled if they were aged 18 to 70 with primary CNLC stage IIb/IIIa uHCC, Child-Pugh classification A or B (≤7 points) and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. The patients received donafenib (100 mg po Bid), camrelizumab (200 mg iv Q3W) and TACE for up to 4 cycles (usually 2 cycles, increased to 3 or 4 cycles if necessary), followed by investigator assessment. The primary endpoint was the rate of major pathologic response (MPR), defined as ≤10% residual viable tumor in postoperative specimens. The secondary endpoints were the R0 resection rate, event-free survival (EFS), objective response rate (ORR) and disease control rate (DCR) by mRECIST criteria, and safety. Results: Sixteen patients, 11 men (68.8%) and five women (31.2%), of median age 58 years (range 49-70 years) were enrolled from May 2021 to July 2022. At the data cut-off (November 2022), one patient was still awaiting surgery, whereas 12 (80.0%) of the remaining 15 patients were successfully converted to resectable. Of the 12 patients who underwent successful hepatectomy (R0 resection), 6 (50%) achieved MPR. Based on mRECIST criteria, the ORR was 81.3%, and the DCR was 93.8%. Median EFS was 9.0 months (95%CI 7.1-10.9 months). Most treatment-related adverse events (TRAEs) were grade 1-2. Grade 3 TRAEs occurred in 4 patients. No patient experienced a Grade 4 or 5 TRAE. Conclusions: These preliminary results suggested that conversion therapy with donafenib, camrelizumab and TACE was safe and effective for uHCC. Clinical trial information: ChiCTR2100043462 .[Table: see text]
Preclinical development of RAG1-40-31L: A novel small activating RNA-lipid conjugate targeting tumor suppressor gene p21 for treatment of non-muscle invasive bladder cancer.
Authors: Harri Jarvelainen, Wei-Hsiang Lin, Moorim Kang, Xiaojie Zhou, Robert F. Place, Long-Cheng Li
Journal: Journal of Clinical Oncology (2023)

e16620 Background: Loss-of-function of tumor suppressor genes are the dominant driving force in tumorigenesis. Restoration in function and/or expression of these genes holds tremendous therapeutic potential in cancer treatment. Bladder cancer is the 9 th leading cause of cancer-related deaths in the United States in which ~75% of all newly diagnosed cases are non-muscle invasive bladder cancer (NMIBC). Standard-of-care includes intravesical installation of Bacillus Calmette-Guerin following tumor resection with an expected failure rate of ~50% within 6 months for patients with high-grade tumors. RNA activation (RNAa) is a mechanism in which short RNA duplexes termed small activating RNA (saRNA) induce gene transcription by targeting non-coding regulatory sequence ( i.e., promoters) embedded in chromatin. Thus, saRNA-induced overexpression of p21 WAF1/CIP1 (p21) – a tumor suppressor of several anti-growth pathways – may hold therapeutic potential in bladder cancer. Through conjugation of a novel lipid ( i.e., C5X5), we have created a p21-targeting saRNA drug candidate referred to as RAG01-40-31L for delivery to bladder cancer cells in vivo. The aim of this work was to characterize the intravesical administration of RAG01-40-31L on p21 induction and its anti-tumor potential in NMBIC models. Methods: In vitro expression analyses were performed to investigate p21 induction via saRNA in KU7 and T24 bladder cancer cell lines by RT-qPCR and immunoblot analysis. Cell cycle analysis and tumorigenicity assays examined impact of RAG1-40-31L on cancer cell growth. Orthotopic human bladder tumors were established in female BALB/c nude mice using the recombinant cell line KU7 engineered to overexpress luciferase reporter. Tumor growth was monitored in live animals via luciferase bioluminescence using an in vivo imaging system. Plasma and tissue were harvested for drug exposure and expression analytics. Results: In vitro analyses indicated RAG1-40-31L activated p21 expression by approximately 6-fold and inhibited bladder cancer cell growth ( i.e., cell cycle arrest, apoptosis, and senescence) in a dose-dependent manner with low nanomolar potency. Intravesical administration of RAG1-40-31L (3 times per week for 2 weeks) inhibited growth of orthotopic tumors by 65% in mouse bladder models. Single-dose pharmacokinetics demonstrated a half-life (t 1/2 ) of ~114 h with minimal systemic exposure (~0.05% of that of bladder tissue). Conclusions: These data constitute a preclinical proof-of-concept for saRNA as a novel p21-targeting modality in the treatment of cancer. The C5X5 lipid conjugate appears to be a viable approach to enhance oligonucleotide delivery and activity in bladder cancer. Preclinical safety assessment studies to enable clinical trials of RAG01-40-31L are currently underway.